The Duality of Angiogenesis: Implications for Therapy of Human Disease Betsy N. Perry, Jack L. Arbiser  Journal of Investigative Dermatology  Volume 126, Issue 10, Pages 2160-2166 (October 2006) DOI: 10.1038/sj.jid.5700462 Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Tumors recruit endothelial precursor cells through multiple ligands. Tumor cells produce numerous chemokines, such as ang-2, stromal cell-derived factor-1, and soluble kit ligand. Soluble kit ligand is generated from cell membranes by the activity of matrix metalloproteinase-9. Endothelial precursors required Hox A9 for survival and growth, as well as cathepsin L for migration from bone marrow to the site of tumors. Journal of Investigative Dermatology 2006 126, 2160-2166DOI: (10.1038/sj.jid.5700462) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Paradox of opposing activities of ang-1 and ang-2. Both ang-1 and ang-2 act at the tie-2 receptor, and stimulate phosphoinositol 3 kinase/akt signaling. However, ang-1 stabilizes endothelium and inhibits vascular permeability, whereas ang-2 destabilizes endothelium and increases vascular permeability. Ang-2 may act by not only stimulating phosphoinositol 3 kinase/akt, but also by inducing reactive oxygen. This may occur at the level of crosstalk or even heterodimerization. Journal of Investigative Dermatology 2006 126, 2160-2166DOI: (10.1038/sj.jid.5700462) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Mode of carcinogenesis and tumor suppressor profile determine signaling pathway and sensitivity to TNF-α, which kills tumor cells in part through generation of reactive oxygen. Journal of Investigative Dermatology 2006 126, 2160-2166DOI: (10.1038/sj.jid.5700462) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Dual role of hydrogen peroxide and superoxide in angiogenesis.Nox family members (cytochrome b558) convert molecular oxygen to superoxide. Superoxide stimulates production of ang-2, which results in recruitment of endothelial precursor cells. Superoxide is metabolized to hydrogen peroxide by manganese superoxide dismutase. Hydrogen peroxide stimulates VEGF through an p38mitogen-activated protein kinase/HIF 1-α pathway. Increased VEGF production results in increased recruitment of local endothelium. Hydrogen peroxide is further metabolized to water by catalase and glutathione peroxidase. Journal of Investigative Dermatology 2006 126, 2160-2166DOI: (10.1038/sj.jid.5700462) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions